Detection and Mapping of Quantitative Trait Loci that Determine Responsiveness

Exposure to 70% N2O evokes a robust antinociceptive effect in C57BL/6 (B6) but not in DBA/2 (D2) inbred mice. This study was conducted to identify quantitative trait loci (QTL) in the mouse genome that might determine responsiveness to N2O. Offspring from the F2 generation bred from B6 and D2 progenitors exhibited a broad range of responsiveness to N2O antinociception as determined by the acetic acid-induced abdominal constriction test. QTL analysis was then used to dissect this continuous trait distribution into component loci, and to map them to broad chromosomal regions. To this end, 24 spleens were collected from each of the following four groups: male and female F2 mice responding to 70% N2O in oxygen with 100% response (high-responders); and male and female F2 mice responding with 0% response (low-responders). Genomic DNA was extracted from the spleens and genotyped with simple sequence length polymorphism MapPairs markers. Findings were combined with findings from the earlier QTL analysis from BXD recombinant inbred mice [Brain Res 725 (1996) 23]. Combined results revealed two significant QTL that influence responsiveness to nitrous oxide on proximal chromosome 2 and distal chromosome 5, and one suggestive QTL on midchromosome 18. The chromosome 2 QTL was evident only in males. A significant interaction was found between a locus on chromosome 6 and another on chromosome 13 with a substantial effect on N2O antinociception

Probing small-x parton densities in proton- proton (-nucleus) collisions in the very forward direction

We present calculations of several pp scattering cross sections with potential applications at the LHC. Significantly large rates for momentum fraction, x, as low as 10^-7 are obtained, allowing for possible extraction of quark and gluon densities in the proton and nuclei down to these small x values provided a detector with good acceptance at maximal rapidities is used.Comment: 14 pages, LaTeX, 12 figures, uses revtex.st

Population genetic analysis of the Plasmodium falciparum 6-cys protein Pf38 in Papua New Guinea reveals domain-specific balancing selection

<p>Abstract</p> <p>Background</p> <p>The <it>Plasmodium falciparum </it>merozoite surface protein Pf38 is targeted by antibodies of malaria immune adults and has been shown to be under balancing (immune) selection in a Gambian parasite population, indicating potential as a malaria vaccine candidate. This study explores the population genetics of <it>Pf</it>38 in Papua New Guinea, to determine the extent and geographic distribution of diversity and to measure selective pressure along the length of the gene.</p> <p>Methods</p> <p>Using samples collected during community-based cross-sectional surveys in the Mugil and Wosera regions, the <it>Pf38 </it>genes of 59 <it>P. falciparum </it>isolates were amplified and sequenced. These sequences, along with previously sequenced Gambian and laboratory isolates, were then subjected to an array of population genetic analyses, examining polymorphisms, haplotype diversity and balancing selection. In addition to whole-gene analysis, the two 6-cys domains were considered separately, to investigate domain specific polymorphism and selection.</p> <p>Results</p> <p>Nineteen polymorphic sites were identified in the <it>Pf </it>38 gene. Of these, 13 were found in the Gambia, 10 in Mugil and 8 in Wosera. Notably, the majority of common polymorphisms were confined to domain I. Although only moderate levels of nucleotide diversity were observed, the haplotype diversity was high in all populations, suggesting extensive recombination. Analyses of the full-length sequence provided only modest evidence for balancing selection. However, there was a strong contrast between domain I, which showed strong evidence for positive balancing selection, and domain II which was neutral. Analyses of the geographic distribution of Pf38 haplotypes showed that four haplotypes accounted for the majority of sequences found world-wide, but there were many more haplotypes unique to the African than the PNG populations.</p> <p>Conclusion</p> <p>This study confirmed previous findings that <it>Pf38 </it>is a polymorphic gene under balancing selection. However, analysing polymorphism and selection across the length of the gene painted a considerably different picture. Domain I is highly polymorphic and the target of significant balancing selection. In contrast, domain II is relatively conserved and does not show evidence of immune selective pressure. The findings have implications for future population genetic studies on vaccine candidates, showing that the biological context must also be considered as a framework for analysis.</p

The structure of F₁-ATPase from Saccharomyces cerevisiae inhibited by its regulatory protein IF₁.

The structure of F₁-ATPase from Saccharomyces cerevisiae inhibited by the yeast IF₁ has been determined at 2.5 Å resolution. The inhibitory region of IF₁ from residues 1 to 36 is entrapped between the C-terminal domains of the α(DP)- and β(DP)-subunits in one of the three catalytic interfaces of the enzyme. Although the structure of the inhibited complex is similar to that of the bovine-inhibited complex, there are significant differences between the structures of the inhibitors and their detailed interactions with F₁-ATPase. However, the most significant difference is in the nucleotide occupancy of the catalytic β(E)-subunits. The nucleotide binding site in β(E)-subunit in the yeast complex contains an ADP molecule without an accompanying magnesium ion, whereas it is unoccupied in the bovine complex. Thus, the structure provides further evidence of sequential product release, with the phosphate and the magnesium ion released before the ADP molecule.Support for this work was provided by the Medical Research Council, UK, including a PhD studentship (to G.C.R.) and a Career Training Fellowship (to J.V.B.), by the European Drug Initiative in Channels and Transporters (EDICT; to J.E.W.), and by a grant from NIH no. R01GM66223 to D.M.M

Report of the panel on earth rotation and reference frames, section 7

Objectives and requirements for Earth rotation and reference frame studies in the 1990s are discussed. The objectives are to observe and understand interactions of air and water with the rotational dynamics of the Earth, the effects of the Earth's crust and mantle on the dynamics and excitation of Earth rotation variations over time scales of hours to centuries, and the effects of the Earth's core on the rotational dynamics and the excitation of Earth rotation variations over time scales of a year or longer. Another objective is to establish, refine and maintain terrestrial and celestrial reference frames. Requirements include improvements in observations and analysis, improvements in celestial and terrestrial reference frames and reference frame connections, and improved observations of crustal motion and mass redistribution on the Earth

Kantowski-Sachs String Cosmologies

We present new exact solutions of the low-energy-effective-action string equations with both dilaton $\phi$ and axion $H$ fields non-zero. The background universe is of Kantowski-Sachs type. We consider the possibility of a pseudoscalar axion field $h$ ($H=e^\phi (dh)^{*}$) that can be either time or space dependent. The case of time-dependent $h$ reduces to that of a stiff perfect-fluid cosmology. For space-dependent $h$ there is just one non-zero time-space-space component of the axion field $H$, and this corresponds to a distinguished direction in space which prevents the models from isotropising. Also, in the latter case, both the axion field $H$ and its tensor potential $B$ ($H=dB$) are dependent on time and space yet the energy-momentum tensor remains time-dependent as required by the homogeneity of the cosmological model.Comment: 23 pages, REVTEX, 6 figures available on reques

Aeronautic Instruments. Section V : Power Plant Instruments

Part 1 gives a general discussion of the uses, principles, construction, and operation of airplane tachometers. Detailed description of all available instruments, both foreign and domestic, are given. Part 2 describes methods of tests and effect of various conditions encountered in airplane flight such as change of temperature, vibration, tilting, and reduced air pressure. Part 3 describes the principal types of distance reading thermometers for aircraft engines, including an explanation of the physical principles involved in the functioning of the instruments and proper filling of the bulbs. Performance requirements and testing methods are given and a discussion of the source of error and results of tests. Part 4 gives methods of tests and calibration, also requirements of gauges of this type for the pressure measurement of the air pressure in gasoline tanks and the engine oil pressure on airplanes. Part 5 describes two types of gasoline gauges, the float type and the pressure type. Methods of testing and calibrating gasoline depth gauges are given. The Schroeder, R. A. E., and the Mark II flowmeters are described

Enhancing therapeutic vaccination by blocking PD-1–mediated inhibitory signals during chronic infection

Therapeutic vaccination is a potentially promising strategy to enhance T cell immunity and viral control in chronically infected individuals. However, therapeutic vaccination approaches have fallen short of expectations, and effective boosting of antiviral T cell responses has not always been observed. One of the principal reasons for the limited success of therapeutic vaccination is that virus-specific T cells become functionally exhausted during chronic infections. We now provide a novel strategy for enhancing the efficacy of therapeutic vaccines. In this study, we show that blocking programmed death (PD)-1/PD-L1 inhibitory signals on exhausted CD8+ T cells, in combination with therapeutic vaccination, synergistically enhances functional CD8+ T cell responses and improves viral control in mice chronically infected with lymphocytic choriomeningitis virus. This combinatorial therapeutic vaccination was effective even in the absence of CD4+ T cell help. Thus, our study defines a potent new approach to augment the efficacy of therapeutic vaccination by blocking negative signals. Such an approach may have broad applications in developing treatment strategies for chronic infections in general, and perhaps also for tumors